(+/-)-BENZOABIKOVIROMYCIN, A POTENTIAL ANTIVIRAL AGENT SYNTHESIZED BY THE PALLADIUM-CATALYZED RING EXPANSION OF 2-ALKYNYL-2-HYDROXYBENZOCYCLOBUTENONES

Abikoviromycin [(4R,4aS)-5-(1’E)-ethylidene-2,3-dihydro-l,5-pyridine 4,4a-oxide] is an antiviral and antifungal antibiotic isolated from culture broths of Streptomyces abikoensis and Streptomyces rubescens and more recently from Streptomyces sp. NA-337. It was shown to be identical with latumcidin, isolated in 1958 from the culture broth of Streptomyces reticular liatumcidicus. Given its interesting biological acitivity and novel structure, abikoviromycin should have attracted the attention of both synthesis and medicinal chemists interested in probing further the chemical and biological properties of this highly functionalized molecule, as well as its analogues. However, abikoviromycin is highly unstable and polymerizes rapidly upon isolation even at –50 °C. It is readily decomposed by heat, by acid, or on standing in the dry state. This extreme reactivity has probably precluded in-depth studies of the molecule, and therefore, it is not surprising that there have been no synthetic efforts in the area published to date. Starting from the premise that the chemical reactivity of abikoviromycin is associated with polymerization of the diene–imine portion of the molecule, masking of the 6,7-double bond as part of a benzene ring might lead to increased stability of the resulting molecule while still retaining aspects of the biological activity. A brief and concise synthesis of racemic benzoabikoviromycin is described on the basis of the previously developed facile and stereoselective palladium(2+)-catalyzed ring expansion of 2-alkynyl-2-hydroxybenzocyclobutenone monoketals to alkylideneindandione monoketals. © 1990, American Chemical Society. All rights reserved.